Cyanoalkyl-5-(substituted triphenylmethyl)picolinate

ABSTRACT

Disclosed herein are novel 5-tritylpicolinic acids, amides, esters and pharmaceutically acceptable salts thereof. Also disclosed are methods for the use of said novel compounds as anti-acne agents.

This is a division, of application Ser. No. 636,010 filed Nov. 28, 1975now U.S. Pat. No. 4,044,140.

This invention relates to a novel class of compounds useful as anti-acneagents. More particularly, this invention relates to 5-(substitutedtriphenylmethyl) picolinic acids, esters, amides and pharmaceuticallyacceptable salts thereof, and to their use in the treatment andalleviation of acne.

The tangible embodiments of this invention are represented by thefollowing structural formula: ##STR1## and the pharmaceuticallyacceptable salts thereof, wherein R is hydrogen or alkyl; each R₁ is amember selected from the group consisting of hydrogen, halogen, hydroxy,alkyl, alkoxy, trifluoromethyl and phenyl; Q is a member selected fromthe group consisting of hydroxy, cyanoalkoxy, alkoxy, --O-alkylene NR₂R₃, glyceryl, NR₂ R₃, --NR₂ -alkylene--OH; and R₂ and R₃ which may bethe same or different are members selected from the group consisting ofhydrogen and alkyl or R₂ and R₃ together with the amido nitrogen atommay form a 5 to 7 membered heterocyclic ring which may contain a secondheteroatom selected from the group consisting of oxygen and nitrogen.

Although the compounds of this invention may more properly be named as2-pyridine carboxylic acids, such compounds will be named according totheir trivial nomenclature. Thus, for ease in nomenclature and for amore readily recognizable term to one of ordinary skill in the art, thecompounds are herein designated as picolinic acids.

As used herein the term "alkyl" means a straight, branched chain orcyclized hydrocarbon having up to 12 carbon atoms. The term "alkoxy"means a straight, branched chain or cyclized hydrocarbon which is bondedto an oxygen atom by a single bond. When such terms are modified by theterm "lower" then such radicals contain up to six carbon atoms.Representative of the alkyl and alkoxy groups are methyl, ethyl,n-butyl, t-butyl, octyl, dodecyl, isopropyl, cyclopropyl, cyclopentyl,cycloheptyl, cyclooctyl, methoxy, ethoxy, n-butyloxy, t-butyloxy,octyloxy, dodecyloxy, isopropyloxy, cyclopropyloxy, cyclopentyloxy,cycloheptyloxy, cyclooctyloxy, and the like, with the lower alkyl andlower alkoxy groups being preferred.

The term "--O-alkylene-NR₂ R₃ ", which is sometimes also describedherein as "aminoalkyloxy", represents an alkylene group consisting of adivalent straight, branched or cyclized hydrocarbon having up to 12carbon atoms, which is between an oxygen atom and the NR₂ R₃ group.Preferably, the alkylene moiety has up to six carbon atoms. Among thepreferred "--O-alkylene-NR₂ R₃ " groups are: aminoethoxy,aminopropyloxy, aminovaleryloxy, mono and dialkylaminoethoxy, mono anddialkylaminovaleryloxy, piperidinoethoxy, morpholinoethoxy,piperazinoethoxy, pyrrolidinoethoxy, morpholinopropyloxy,morpholinovaleryloxy and piperazinoisopropyloxy.

Examples of groups represented by "NR₂ R₃ " are amino, mono anddialkylamino, morpholino, pyrrolidino, piperidino and piperazino.

In view of the foregoing definition of the terms "NR₂ R₃ " and"O-alkylene-NR₂ R₃ ", the definition of the terms "NR₂ -alkylene-OH" and"O-alkylene-CN" (cyanoalkoxy) are obvious.

The term "glyceryl" is the radical generally shown as --OCH₂ CHOHCH₂ OH.

Exemplary of the salts of the picolinic acids of Formula I, i.e. wherein"Q" represents hydroxy, are those formed with alkali metals, alkalineearth metals and non-toxic organic bases such as N-methyl glucamine andalcoholamines, preferably diethanolamine.

In those instances wherein the "R" substituent on the picolinic acidmoiety is an alkyl group, it is preferably located at the 3-position ofthe pyridine ring.

The compounds of this invention may be prepared by methods generallyknown in the art. For example, in the Journal of the American ChemicalSociety 71, 387-390 (1949) is set forth a convenient procedure forpreparing 5-triphenylmethyl-2-chloropyridine. In an analogous mannerR-substituted-5-(R₁ -substituted triphenylmethyl)-2-halogeno pyridinesmay be prepared. Treatment of the latter compounds with cuprous cyanideconverts them to the corresponding 2-cyano analog from which theR-substituted-5-(R₁ -substituted triphenylmethyl)-picolinic acid may beprepared by hydrolysis. The foregoing reaction sequence is depicted bythe following reaction sequence: ##STR2## wherein R and R₁ are aspreviously defined and Y represents a halogen.

Standard techniques, such as by heating compound II and cuprous cyanideat elevated temperatures, preferably in the presence of an inert organicsolvent, for about 2 to 10 hours, are utilized in the first step of theabove reaction. For example, the reaction is very smoothly effected inrefluxing dimethylformamide in from about 4 to about 6 hours. Isolationof the 2-cyano analog (III) may be accomplished by standard extractiontechniques after the reaction mixture has been quenched; preferably byutilization of a non-water miscible solvent, e.g. benzene, toluene,ethyl ether or the like.

The crude 2-cyano intermediates (III) may directly be converted to theacid via an intermediate alkali metal salt which is then converted toits desired acid form. Standard purification through salt formation andhydrolysis techniques well known to those of ordinary skill in the artmay be employed.

To prepare compounds of this invention wherein Q is an activated ester,it is advantageous to utilize the following reaction sequence: ##STR3##wherein R, R₁ and alkylene are as previously defined, and X is ahalogen.

Conversion of an R-substituted 5-(R₁ -triphenylmethyl)-picolinic acid(Ia) to the corresponding cyanomethyl ester (Ib) is usually effected bytreating the acid at an elevated temperature with a halogenoacetonitrilein the presence of an acid acceptor, such as triethylamine. The reactionis, advantageously, effected in a non-reactive organic solvent such asacetone, methyl ethyl ketone, or the like. The reaction is allowed toproceed for from about 5 to about 20 hours, the reaction mixture iscooled and filtered. The filtrate is concentrated to a residue andtriturated with water to yield the desired cyanomethyl ester (Ib). Thecyanomethyl ester is a key intermediate from which nearly all of thecompounds having the various Q substituents may be prepared. Forexample, subjecting the cyanomethyl ester to a conventional basecatalyzed alcoholysis permits the alcohol to replace the cyanomethylmoiety thereby yielding an alkyl ester derivative. In like manner, bytreating the cyanomethyl ester with a dialkylamine at an elevatedtemperature, the corresponding dialkylamide may be prepared. In fact,from the cyanomethyl intermediate the compounds of this inventionwherein Q=alkoxy, --O-alkylene-NR₂ R₃, --NR₂ R₃, and --NR₂-alkyklene--OH may be prepared by the use of the transesterification andamidation techniques. Of course, in those instances wherein thetransesterification process designed to produce an amine having areactive hydrogen, in such reactions the amine groups are firstprotected (e.g. by standard benzylation procedures) and subsequent tothe transesterification, the benzyl or other protective groups arereadily cleaved by standard techniques well known in the art. Similarly,when "Q" represents a hydroxyalkylamine, the terminal hydroxy moietymust first be protected e.g. with hydroxy (ether) protecting group andthen following transesterification the protecting group removed. Theseprocedures are conducted according to techniques well known in the art.

In those instances wherein it is desired to prepare amides wherein "NR₂R₃ " is representative of NH₂ , such R-substituted 5-(R₁-diphenylmethyl)picolinamides may be prepared by saponification of thecorresponding R-substituted 5-(R₁ -diphenylmethyl)-2-cyanopyridine andmay be isolated by conventional means.

To prepare compounds of this invention wherein Q is a glyceryl ester,several different routes may be utilized, the choice being determined bythe ready availability of the required starting compounds.Preferentially, the ester is prepared by the hydrolysis of analkylidenedioxypropyl ester of an appropriately substitutedtriphenylmethyl picolinic acid. The alkylidenedioxypropyl ester isgenerally prepared by transesterification wherein a reactive alkyl ester(Ib) such as a cyanomethyl ester is transesterified by a cyclic acetalof glycerol (IV). The transesterification is generally effected byheating the reactive ester with the cyclic acetal of glycerol (IV) inthe presence of catalytic amounts of tertiary amine catalyst, such astriethylamine at temperatures in the range of 80°-200° C, about 100° Cbeing preferred. Due to the nature of the transesterification it isadvantageous to employ a large excess of cyclic acetal to drive thereaction to completion. Hydrolysis of the alkylidenedioxypropyl ester ofthe R-substituted 5-(R₁ -triphenylmethyl)-picolinic acid (V) to yieldthe desired glyceryl ester (Ic) is usually effected by conventionaltechniques, such as by heating the intermediate in the presence of anacid. For example, by heating the intermediate in dilute acetic aciduntil the reaction is substantially complete and isolating the glycerylester by means known to the art.

The foregoing reaction sequence may be depicted as follows: ##STR4##wherein R and R₁ are as previously defined, and R₄ and R₅ are loweralkyl.

The remaining Q substituents may be prepared by standard amidation andesterification procedures well known in the art. The compounds of thisinvention having a lower alkyl group at the 3-position may be preparedas follows: A 2-amino 3-lower alkyl pyridine (e.g. 2-amino-β-picoline)is reacted with nitrous acid to yield the corresponding 3-lower alkylpyridone. The latter compound may be converted to the corresponding3-lower alkyl 5-triphenylmethyl picolinic acid by the procedure setforth hereinabove.

EXAMPLE I 5-(Triphenylmethyl)-Picolinic Acid A.2-Bromo-5-(Triphenylmethyl)-Pyridine

Heat at reflux for 3 hours a mixture of 50.6 g.5-(triphenylmethyl)-2-pyridone and 171 g. phosphorous oxybromide. Pouronto ice and stir on steam bath to decompose excess phosphorousoxybromide. Filter, dry solids, and triturate the product with benzeneand ethanol to obtain the product of this example, m.p. 273°-276°.

In a similar manner, subject an equivalent quantity of the followingcompounds to the process set forth above to obtain thereby thecorresponding 2-bromo-pyridine.

5-[(4-biphenyl)diphenylmethyl]-2-pyridone,

5-[(4-chlorophenyl)diphenylmethyl]-2-pyridone,

5-[tris-(4-chlorophenyl)methyl]-2-pyridone,

5-[(4-methylphenyl)diphenylmethyl]-2-pyridone,

5-[bis-(4-fluorophenyl)phenylmethyl]-2-pyridone,

5-[(4-methoxyphenyl)diphenylmethyl]-2-pyridone,

5-[(4-trifluoromethylphenyl)diphenylmethyl]-2-pyridone,

3-methyl-5-[(4-trifluoromethylphenyl)diphenylmethyl]-2-pyridone,

5-[(3-bromophenyl)diphenylmethyl]-2-pyridone,

5-[tris-(3-fluorophenyl)methyl]-2-pyridone,

5-[(3-ethylphenyl)diphenylmethyl]-2-pyridone,

5-[bis-(3-fluorophenyl)phenylmethyl]-2pyridone,

5-[(3-propoxyphenyl)diphenylmethyl]-2-pyridone,

5-[tris-(3-trifluoromethylphenyl)methyl]-2-pyridone,

3-ethyl-5-[(3-trifluoromethylphenyl)diphenylmethyl]-2-pyridone,

5-[(2-chlorophenyl)diphenylmethyl]-2-pyridone,

5-[(2-isopropylphenyl)diphenylmethyl]-2-pyridone,

5-[bis-(2-fluorophenyl)phenylmethyl]-2-pyridone,

5-[tris-(2-methylphenyl)methyl]-2-pyridone,

5-[(2-ethoxyphenyl)diphenylmethyl]-2-pyridone, and

5-[(2-trifluoromethylphenyl)diphenylmethyl]-2-pyridone.

B. 5-(Triphenylmethyl)-Picolinic Acid

Heat at reflux a mixture of 46.9 g 2-bromo-5-(triphenylmethyl)-pyridineand 21.5 g cuprous cyanide in 450 ml. dimethylformamide for 51/2 hr.Pour onto a mixture of ice and 200 ml. ethylene diamine, extract withbenzene, dry the benzene extracts, and concentrate. The crude, viscous2-cyano-5-(triphenylmethyl)-pyridine may be purified by crystallizationfrom acetonitrile to yield a product melting at about 176°-179° or thecompound may be converted directly to the acid via the potassium salt byheating it at reflux with 20 g potassium hydroxide pellets in 120 ml. H₂O and 400 ml. ethylene glycol for 15 hr. Filter the hot solution, coolthe filtrate which precipitates the potassium salt of the acid. Filterthe salt and wash with ethylene glycol, suspend in water, acidify andheat for 1 hr. Filter the acid, dry and recrystallize from acetonitrile,m.p. 215°-217°.

Additional acid is obtained by concentrating the ethylene glycolfiltrate of the potassium salt and acidifying.

In addition to the "free" carboxylic acids set forth, thepharmaceutically acceptable salts of the acids are also useful asanti-acne agents. The salts may be prepared in the conventional manner,such as, by reacting the acid with an excess of base in a suitablesolvent. Isolation of the salts is achieved by methods generally used inthe art. Exemplary of such bases are the hydroxides, carbonates orbicarbonates of alkali metals, alkaline earth metals and organic basessuch as amines (e.g. triethylamine), or, preferably, an alcoholaminesuch as diethanolamine.

In a similar manner, subject an equivalent quantity of the followingcompounds to the process set forth above to obtain thereby thecorresponding R-substituted-5-(R₁ -substituted)-picolinic acid.

2-bromo-5-[(4-biphenyl)diphenylmethyl]-pyridine,

2-bromo-5-[(4-chlorophenyl)diphenylmethyl]-pyridine,

2-bromo-5-[tris-(4-chlorophenylmethyl)]-pyridine,

2-bromo-5-[(4-methylphenyl)diphenylmethyl]-pyridine,

2-bromo-5-[bis-(4-fluorophenyl)phenylmethyl]-pyridine,

2-bromo-5-[(4-methoxyphenyl)diphenylmethyl]-pyridine,

2-bromo-5-[(4-trifluoromethylphenyl)diphenylmethyl]-pyridine,

2-bromo-3-methyl-5-[ (4-trifluoromethylphenyl)diphenylmethyl]-pyridine,

2-bromo-5-[(3-bromophenyl)diphenylmethyl]-pyridine,

2-bromo-5-[tris-(3-fluorophenyl)methyl]-pyridine,

2-bromo-5-[(3-ethylphenyl)diphenylmethyl]-pyridine,

2-bromo-5-[bis(3-fluorophenyl)phenylmethyl]-pyridine,

2-bromo-5-[(3-propoxyphenyl)diphenylmethyl]-pyridine,

2-bromo-5-[tris-(3-trifluoromethylphenyl)methyl]-pyridine,

2-bromo-3-ethyl-5-[(3-methylphenyl)diphenylmethyl]-pyridine,

2-bromo-5-[(2-chlorophenyl)diphenylmethyl]-pyridine,

2-bromo-5-[(2-isopropylphenyl)diphenylmethyl]-pyridine,

2-bromo-5-[bis-(2-fluorophenyl)phenylmethyl]-pyridine,

2-bromo-5-[tris-(2-methylphenyl)methyl]-pyridine,

2-bromo-5-[(2-ethoxyphenyl)diphenylmethyl]-pyridine, and

2-bromo-5-[(2-trifluoromethylphenyl)diphenylmethyl]-pyridine.

EXAMPLE II Cyanomethyl 5-(Triphenylmethyl)-Picolinate

To a stirred mixture of 5 g. 5-triphenylmethyl)picolinic acid and 6.1 g.triethylamine in 150 ml. acetone add 4.5 g of chloroacetonitrile. Heatthe resulting mixture at reflux 15 hrs., cool, filter. Concentrate thefiltrate to a residue and triturate residue with water, dry.Recrystallize twice from isopropyl ether-ethanol to obtain the productof this example, m.p. 173°-175°.

In a similar manner, subject an equivalent quantity of the followingcompounds to the process set forth above to obtain thereby thecorresponding cyanomethyl R-substituted-5-(R₁-substituted-triphenylmethyl)-picolinate:

5-[(4-biphenyl)diphenylmethyl]-picolinic acid,

5-[(4-chlorophenyl)diphenylmethyl]-picolinic acid,

5-[tris-(4-chlorophenyl)methyl]-picolinic acid,

5-[(4-methylphenyl)diphenylmethyl]-picolinic acid,

5-[bis-(4-fluorophenyl)phenylmethyl]-picolinic acid,

5-[(4-methoxyphenyl)diphenylmethyl]-picolinic acid,

5-[4-(trifluoromethylphenyl)diphenylmethyl]-picolinic acid,

3-methyl-5-[4-(trifluoromethylphenyl)diphenylmethyl]-picolinic acid,

5-[(3-bromophenyl)diphenylmethyl]-picolinic acid,

5-[tris-(3-fluorophenyl)methyl]-picolinic acid,

5-[(3-ethylphenyl)diphenylmethyl]-picolinic acid,

5-[bis-(3-fluorophenyl)phenylmethyl]-picolinic acid,

5-[(3-propoxyphenyl)diphenylmethyl]-picolinic acid,

5-[tris-(3-trifluoromethylphenyl)methyl]-picolinic acid,

3-ethyl-5-[(3-methylphenyl)diphenylmethyl]-picolinic acid,

5-[(2-chlorophenyl)diphenylmethyl]-picolinic acid,

5-[(2-isopropylphenyl)diphenylmethyl]-picolinic acid,

5-[bis(2-fluorophenyl)phenylmethyl]-picolinic acid,

5-[tris-(2-methylphenyl)methyl]

5-[(2-ethoxyphenyl)diphenylmethyl]-picolinic acid, and

5-[(2-trifluoromethylphenyl)diphenylmethyl]-picolinic acid.

EXAMPLE III Methyl 5-(Triphenylmethyl)-Picolinate

Heat at reflux 4 gm. (0.01 mole) ofcyanomethyl-5-(triphenylmethyl)picolinate and 2 ml. triethylamine in 50ml. methanol for 4 hr. Remove methanol under reduced pressure. Trituratesolid residue with water and recrystallize from ethylacetate - isopropylether, to obtain the product of this example, m.p. 160°-164°.

In a similar manner, subject an equivalent quantity of the followingcompounds to the process set forth above to obtain thereby thecorresponding methyl R -substituted-5-[R₁ -triphenylmethyl]-picolinate:

cyanomethyl 5-[(4-biphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[(4-chlorophenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[tris-(4-chlorophenyl)methyl]-picolinate,

cyanomethyl 5-[(4-methylphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[bis-(4-fluorophenyl)phenylmethyl]-picolinate,

cyanomethyl 5-[(4-methoxyphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[4-(trifluoromethylphenyl)diphenylmethyl]-picolinate,

cyanomethyl3-methyl-5-[4-(trifluoromethylphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[(3-bromophenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[tris-(3-fluorophenyl)methyl]-picolinate,

cyanomethyl 5-[(3-ethylphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[bis-(3-fluorophenyl)phenylmethyl]-picolinate,

cyanomethyl 5-[(3-propoxyphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[tris-(3-trifluoromethylphenyl)methyl]-picolinate,

cyanomethyl 3-ethyl-5-[(3-methylphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[(2-chlorophenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[(2-isopropylphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[bis-(2-fluorophenyl)phenylmethyl]-picolinate,

cyanomethyl 5-[tris-(2-methylphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[(2-ethoxyphenyl)diphenylmethyl]-picolinate, and

cyanomethyl 5-[(2-trifluoromethylphenyl)diphenylmethyl]-picolinate.

In a similar manner by substituting other alcohols, such as ethanol,propanol, isopropanol, n-butanol or alcohols of the general formulaHO-alkylene-NR₂ R₃ for methanol, and by following the process of ExampleIV the corresponding esters may be prepared.

EXAMPLE IV N,N-Diethyl-5-(Triphenylmethyl)-Picolinamide

Heat at reflux for 6 hours a mixture of 0.1 mole ofcyanomethyl-5-(triphenylmethyl)-picolinate and 0.5 moles ofdiethylamine. Cool the reaction mixture, pour into water and extractwith chloroform. Dry the chloroform layer over anhydrous sodium sulfateand evaporate to obtain thereby the product of this example.

In a smilar manner, subject an equivalent quantity of the followingcompounds to the process set forth above to obtain thereby thecorresponding N,N-diethyl-R-substituted-5-(R₁-triphenylmethyl)-picolinamide:

cyanomethyl 5-[(4-biphenyl)-diphenylmethyl]-picolinate,

cyanomethyl 5-[(4-chlorophenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[tris-(4-chlorophenyl)methyl]-picolinate,

cyanomethyl 5-[(4-methylphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[bis-(4-fluorophenyl)phenylmethyl]-picolinate,

cyanomethyl 5-[(4-methoxyphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[(4-trifluoromethylphenyl)diphenylmethyl]-picolinate,

cyanomethyl3-methyl-5-[(4-trifluoromethylphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[(3-bromophenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[tris-(3-fluorophenyl)methyl]-picolinate,

cyanomethyl 5-[(3-ethylphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[bis-(3-fluorophenyl)-phenylmethyl]-picolinate,

cyanomethyl 5-[(3-propoxyphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[tris-(3-trifluoromethylphenyl)methyl]-picolinate,

cyanomethyl 3-ethyl-5-[(3-methylphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[(2-chlorophenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[(2-isopropylphenyl)diphenylmethyl]-picolinate,

cyanomethyl 5-[bis-(2-fluorophenyl)phenylmethyl]-picolinate,

cyanomethyl 5-[tris-(2-methylphenyl)methyl]-picolinate,

cyanomethyl 5-[(2-ethoxyphenyl)diphenylmethyl]-picolinate, and

cyanomethyl 5-[(2-trifluoromethylphenyl)diphenylmethyl]-picolinate.

In a similar manner, by substituting an equivalent quantity of othermono or di-alkylamines or mono or dialcoholamines or heterocyclicamines, such as methylamine, ethylamine, octylamine, dodecylamine,ethanolamine, diethanolamine, piperazine, morpholine, pyrrolidine,piperidine or the like and by following the process set forth in ExampleIV, the corresponding mono or di-alkylamides may be prepared.

EXAMPLE V Glyceryl (5-Triphenylmethyl)-Picolinate A.β-γ-Isopropylidenedioxypropyl(5-triphenylmethyl)-picolinate

Heat with stirring on a steam bath for 11/2 hours a mixture of 4 g ofcyanomethyl 5-(triphenylmethyl)-picolinate, 50 ml. of2,2-dimethyl-1,3-dioxolane-4-methanol and 2 ml. of triethylamine. Treatthe reaction mixture with water, cool and filter to yield the product ofthis step.

B. Glyceryl 5-(Triphenylmethyl)-Picolinate

Heat with stirring on a steam bath for one hour a mixture of 4.5 g. ofβ-γ-isopropylidenedioxypropyl 5-(triphenylmethyl)-picolinate and 90 ml.of 75% acetic acid. Pour the reaction mixture onto ice. Filter anddissolve the resulting solid in ethyl acetate, wash twice with water,dry over MgSO₄ and concentrate, recrystallize from acetonitrile m.p.183°-186° to obtain thereby, the product of this Example.

In a similar manner, subject an equivalent quantity of the compoundsenumerated after Example IV to steps A and B of Example V to obtainthereby the corresponding glyceryl R-substituted-5-(R₁-substituted-triphenylmethyl)-picolinate.

EXAMPLE VI 5-(Triphenylmethyl)-Picolinamide

Dissolve 5 g. of 5-(triphenylmethyl)-2-cyanopyridine in a mixtureconsisting of 50 ml. of water and 1.0 liter of methanol. Add 4 g. ofpotassium hydroxide and heat the mixture at reflux for fifteen (15)hours. Remove the methanol under reduced pressure, triturate the residuewith water and dry the solids obtained thereby. Crystallize the productfrom acetonitrile to obtain the product of this example. m.p. 239°-240°C.

In a similar manner, subject an equivalent quantity of the followingcompounds to the process of Example VI to obtain thereby thecorresponding R-substituted-5-(R₁ -substitutedtriphenylmethyl)-picolinamide:

5-[(4-biphenyl)-diphenylmethyl]-2-cyanopyridine,

5-[(4-chlorophenyl)diphenylmethyl]-2-cyanopyridine,

5-[tris-(4-chlorophenyl)methyl]-2-cyanopyridine,

5-[(4-methylphenyl)diphenylmethyl]-2-cyanopyridine,

5-[bis-(4-fluorophenyl)phenylmethyl]-2-cyanopyridine,

5-[(4-methoxyphenyl)diphenylmethyl]-2-cyanopyridine,

5-[(4-trifluoromethylphenyl)diphenylmethyl]-2-cyanopyridine,

3-methyl-5-[(4-trifluoromethylphenyl)diphenylmethyl]-2-cyanopyridine,

5-[(3-bromophenyl)diphenylmethyl]-2-cyanopyridine,

5-[tris-(3-fluorophenyl)methyl]-2-cyanopyridine,

5-[(3-ethylphenyl)diphenylmethyl]-2-cyanopyridine,

5-[bis-(3-fluorophenyl)phenylmethyl]-2-cyanopyridine,

5-[(3-propoxyphenyl)diphenylmethyl]-2-cyanopyridine,

5-[tris-(3-trifluoromethylphenyl)methyl]-2-cyanopyridine,

3-ethyl-5-[(3-methylphenyl)diphenylmethyl]-2-cyanopyridine,

5-[(2-chlorophenyl)diphenylmethyl]-2-cyanopyridine,

5-[(2-isopropylphenyl)diphenylmethyl]-2-cyanopyridine,

5-[bis-(2-fluorophenyl)phenylmethyl]-2-cyanopyridine,

5-[tris-(2-methylphenyl)methyl]-2-cyanopyridine,

5-[(2-ethoxyphenyl)diphenylmethyl]-2-cyanopyridine, and

5-[(2-trifluoromethylphenyl)diphenylmethyl]-2-cyanopyridine.

The following is a "general" method for preparing "pharmaceuticallyacceptable salts" of the 5-(substituted triphenylmethyl)-picolinicacids:

EXAMPLE VII 5-(Triphenylmethyl)-Picolonic Acid Diethanolamine Salt

Combine 5.5 g. of 5-(triphenylmethyl)-picolinic acid and 1.6 g. ofdiethanolamine in 200 ml. of ethanol and heat to form a solution, thencool to precipitate the salt. Recrystallize from ethanol to give thetitle compound, m.p. 206°-209°.

Acne is a common inflammatory disease in areas of the skin whereinsebaceous glands are largest, most numerous, and most active. It ischaracterized by the appearance of comedones, pustles, papules, inflamednodules, and in extreme cases infected sacs. In acne, Corynebacteriumacnes and Staphylococcus albus, common residents of the skin andsebaceous glands (especially of the adolescent), are known to aggravatethe existing inflammatory condition by releasing enzymes (lipase) whichbreak down the lipid in the sebum with the concomitant release ofirritating free fatty acids (FFA). Thus, an effective anti-acne agentought be one which can prevent or substantially reduce the break-down oflipid in the sebum thereby exerting an anti-inflammatory effect upon theskin. Ideally, the anti-acne agent should be effective topically inorder to minimize the advent of untoward side effects which may occurduring systemic treatment. For instance, frequently used anti-acneagents (e.g. the tetracyclines) are related to side effects which appearwith the long term systemic treatment usually required in treating acne.These adverse effects include gastrointestinal irritation,photosensitivity reactions, dizziness, nausea and vomiting. Thus, thereis need for effective topically applied anti-acne agents. The compoundsof this invention fill such a need.

When tested in vitro by a slightly modified version of the testprocedure described by A. Shalita and V. Wheatley, in J. Invest.Dermatol. 54, 413 (1970), the compounds of this invention were shown tosubstantially inhibit the formation of free fatty acids fromtriglycerides by bacterial lipases, including those formed byCorynebacterium acnes. The free fatty acids produced were assayed by theautomated colorimetric method of C. Dalton and C. Kowalski as describedin Clinical Chem. 13, 744 (1967). Further, the test results clearlydemonstrate that the anti-lipase activity of the compounds of thisinvention is substantially greater than that of hexachlorophene, or thatof tetracycline. Additionally, neither hexachlorophene nor tetracyclineexhibit substantial in vivo topical activity in test animals whereas thecompounds of this invention do. Moreover, the instant compounds aresubstantially devoid of overt skin irritation upon repeated topicaladministration. They also exhibit little systemic toxicity followingrepeated topical application or upon systemic dosing via oral orintraperitoneal administration.

As mentioned, the compounds of this invention are effectiveantibacterial agents, particularly against Corynebacterium acnes and S.albus. Additionally, the compounds of this invention are effectiveagainst other gram-positive organisms and they also are antitrichomonal;they being particularly effective against T. Vaginalis. As such, thecompounds may be used in the conventional manner for treatinggram-positive infections and for treating trichomonal infections.Potency assays and formulations for such uses utilize standardtechniques.

The compounds of this invention are administered topically inpharmaceutical compositions having the conventional excipients. Thecompositions may be in the form of lotions, creams, aerosols andointments. In these compositions, the active compound is present in therange of from about 0.5% to about 10% by weight, administration beingfrom about 2 to about 5 times daily.

As is usually the case wherein a family of compounds exhibit aparticular utility, certain members for one reason or another arepreferred over others. In the instant case, a preferred group ofcompounds are those embraced by formula I wherein R and R₁ are hydrogenand Q is as defined for formula I.

Another preferred group of compounds within the genus defined by formulaI are those wherein R and R₁ are as defined in said claim and Q incombination with the carbonyl to which it is attached forms a glycerylester.

An especially preferred compound within the genus defined by formula Iis the one wherein R and R₁ are hydrogen and Q is hydroxy including thepharmaceutically acceptable salts thereof.

The following Examples (i.e. Examples VIII through XII inclusive) aredirected to topical formulations in which the compounds of thisinvention may be utilized to elicit an anti-acne response. Theformulations are prepared by methods known in the art using the activecompound in the form of a "micronized" solid.

EXAMPLE VIII

    ______________________________________                                        Ointment                  mg/gm                                               ______________________________________                                        5-tritylpicolinic Acid    20.0                                                diethanolamine salt                                                           Propylene Glycol USP      40.0                                                Mineral Oil, USP          50.0                                                White Petrolatum, USP to make                                                                           1.0 g.                                              ______________________________________                                    

EXAMPLE IX

    ______________________________________                                        Ointment                   mg/gm                                              ______________________________________                                        Glyceryl(5-Triphenylmethyl)-                                                                             20.0                                               picolinate                                                                    Propylene Glycol, USP      40.0                                               Stearyl Alcohol, USP       50.0                                               Polyethylene Glycol 400, USP                                                                             600.0                                              Polyethylene Glycol 4000, USP to make                                                                    1.0 g.                                             ______________________________________                                    

EXAMPLE X

    ______________________________________                                        Gel                      mg/gm                                                ______________________________________                                        5-tritylpicolinic Acid   20.0                                                 Propylene Glycol, USP    300.0                                                Polyethylene Glycol, 400 USP                                                                           660.0                                                Butylated Hydroxytoluene 5.0                                                  Carbopol 940P            15.0                                                 Titanium Dioxide, USP    10.0                                                 Sodium Hydroxide, USP    0.7                                                  ______________________________________                                    

EXAMPLE XI

    ______________________________________                                        Cream                      mg/gm                                              ______________________________________                                        5-tritylpicolinic Acid     20.0                                               Stearic Acid, USP          60.0                                               Glyceryl Monostearate, Cosmetic                                                                          100.0                                              Propylene Glycol, USP      50.0                                               Polyoxyethylene Sorbitan Monopalmitate,                                                                  50.0                                               Cosmetic                                                                      Sorbitol Solution, USP     30.0                                               Benzyl Alcohol, N.F.       10.0                                               Purified Water, USP to make                                                                              1.0 gm.                                            ______________________________________                                    

EXAMPLE XII

    ______________________________________                                        Glycol Ointment          mg/gm                                                ______________________________________                                        5-tritylpicolinic Acid   20.0                                                 diethanolamine salt                                                           Propyl Glycol Monostearate                                                                             20.0                                                 Propylene Glycol, USP    100.0                                                White Wax USP            60.0                                                 White Petrolatum qs to make                                                                            1.0 gm.                                              ______________________________________                                    

I claim:
 1. A compound of the formula ##STR5## and the pharmaceuticallyacceptable salts thereof wherein R is hydrogen or alkyl; each R₁ is amember selected from the group consisting of hydrogen, halogen, hydroxy,alkyl, alkoxy, trifluoromethyl and phenyl; Q is a cyanoalkoxy groupwherein said alkyl or alkoxy groups consist of up to 12 carbon atoms. 2.A compound of claim 1 wherein R is alkyl and each R₁ is as defined insaid claim 1 and Q is cyanoalkoxy.
 3. A compound of claim 1 wherein Rand each R₁ are hydrogen and Q is a cyanoalkoxy group.
 4. The compoundof claim 3 wherein Q is cyanomethoxy, said compound beingcyanomethyl-5-(triphenylmethyl) picolinate.
 5. A method of eliciting ananti-acne effect which comprises topically administering atherapeutically effective quantity of a compound of claim 1 of theformula: ##STR6## and the pharmaceutically acceptable salts thereof,wherein R is hydrogen or alkyl; each R₁ is a member selected from thegroup consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy,trifluoromethyl and phenyl; Q is a cyanoalkoxy group wherein said alkylor alkoxy group consists of up to 12 carbon atoms.
 6. A method oftreating as defined in claim 5 wherein R is alkyl and each R₁ is asdefined in said claim, and Q is cyanoalkoxy.
 7. A method of treating asdefined in claim 5 wherein R and each R₁ are hydrogen, and Q iscyanoalkoxy.
 8. The method of treating as defined in claim 7 wherein Qis cyanomethyl, said treatment being effected withcyanomethyl-5-(triphenylmethyl)-picolinate.